1. Field of the Invention
The present invention pertains to a method for healing a wound in a mammal which comprises the steps of (A) providing a therapeutic wound healing composition comprising a therapeutically effective amount of an inhibitor of mono-adenosine diphosphate-ribosyl transferase to inhibit adenosine diphosphate-ribosylation of vascular endothelial growth factor; and (B) contacting the therapeutic wound healing composition with a wound in a mammal. This invention also pertains to wound healing compositions and to methods for preparing and using the wound healing compositions and the pharmaceutical products in which the therapeutic compositions may be used. This invention further pertains to therapeutic dermatological-wound healing compositions useful to minimize and treat diaper dermatitis and to methods for preparing and using the therapeutic dermatological-wound healing compositions.
2. Description of the Background
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography.
Wounds are internal or external bodily injuries or lesions caused by physical means, such as mechanical, chemical, viral, bacterial, or thermal means, which disrupt the normal continuity of structures. Such bodily injuries include contusions, wounds in which the skin is unbroken, incisions, wounds in which the skin is broken by a cutting instrument, and lacerations, wounds in which the skin is broken by a dull or blunt instrument. Wounds may be caused by accidents or by surgical procedures. Patients who suffer major or chronic wounds could benefit from an enhancement in the wound healing process. Wound healing consists of a series of processes whereby injured tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized. Wound healing consists of three major phases: a) an inflammation phase (0-3 days), b) a cellular proliferation phase (3-12 days), and (c) a remodeling phase (3 days-6 months). During the inflammation phase, platelet aggregation and clotting form a matrix which traps plasma proteins and blood cells to induce the influx of various types of cells. During the cellular proliferation phase, new connective or granulation tissue and blood vessels are formed. During the remodeling phase, granulation tissue is replaced by a network of collagen and elastin fibers leading to the formation of scar tissue.
Macrophages play a key role in the induction of angiogenesis in fibroproliferative states, including wound repair, rheumatoid arthritis, and solid tumor development (1-5). Production of angiogenic activity by macrophages depends on the balance of production of positive angiogenic regulators and inhibitors of angiogenesis (6,7,8). Positive angiogenic regulators previously shown to be produced by monocytes and macrophages include the cytokines TNF.alpha. and Il-8 (9,10,11); negative regulators include thrombospondin-1, Ifn.gamma.-inducible protein-10 (.gamma.IP-10) and other as yet uncharacterized protein inhibitors (12,13,14). The mechanisms controlling the balance of positive and negative angiogenesis regulators are not well understood. Non-activated monocytes and macrophages exhibit a non-angiogenic phenotype (1,4). Following activation with agents such as interferon-.gamma. and/or endotoxin (LPS), macrophages express angiogenic activity, characterized by the expression of angiogenic cytokines, as well as of inhibitors of angiogenesis (15,16,17,18). Activated cells also produce and release oxygen radicals, nitric oxide (NO) and their derivatives (17,19). These radicals have been shown to play an important role in regulating the angiogenic phenotype of activated macrophages (20,21). Agents such as Ifn.gamma. and LPS, as well as reduced oxygen tension (hypoxia) and elevated lactate levels, induce macrophages to express angiogenic activity (1-3,9,22). Recently, macrophages in vivo have been shown to express vascular endothelial growth factor (VEGF), an endothelial-specific mitogen that is potently angiogenic (18,23-30).
U.S. Pat. No. 5,510,391 (Elson) discloses a method of treating blood vessel disorders of the skin and skin disorders caused by photo-aging comprising: a) coformulating a pharmaceutical composition wherein the composition contains from 0.01% to 50% vitamin K; and b) applying the pharmaceutical composition topically to treat blood vessel disorders of the skin and skin disorders caused by photo-aging. The blood vessel disorders of the skin and skin disorders caused by photo-aging includes actinic and iatrogenic purpura, lentigines, telangiectasias of the face, spider angiomas, spider veins of the face and leg.